Inorganic acid salts of sibutramine

Abstract

Disclosed are novel inorganic acid salts of sibutramine, which have good physicochemical properties, and crystalline forms thereof. Also disclosed are pharmaceutical compositions comprising the compounds as effective ingredients, methods of preparing the compounds, and the use of the compounds.

1. An inorganic acid salt of sibutramine, which has a structure of the following Chemical Formula 1: 
       
         
           
           
               
               
           
         
         the inorganic acid salt being hydrogen sulfate, bromate, or phosphate monohydrate. 
       
     
     
       2. The inorganic acid salt of sibutramine as set forth in  claim 1 , wherein the sibutramine hydrogen sulfate is a first crystalline sibutramine hydrogen sulfate having an X-ray diffraction pattern in which peaks appear at 2θ values of 6.50, 12.18, 12.38, 12.58, 13.06, 14.00, 16.76, 17.04, 18.06, 19.68, 20.32, 20.63, 21.34, 21.82, 22.28, 22.54, 23.32, 24.50, 25.80, 26.42, 28.24, 28.64, 29.28, and 33.34. 
     
     
       3. The inorganic acid salt of sibutramine as set forth in  claim 1 , wherein the sibutramine hydrogen sulfate is a second crystalline sibutramine hydrogen sulfate having an X-ray diffraction pattern in which peaks appear at 2θ values of 5.73, 6.49, 12.18, 12.51, 13.13, 14.02, 14.79, 16.97, 17.38, 20.62, 21.40, 21.83, 22.31, 22.68, 24.51, 24.88, 25.82, 26.45, and 31.60. 
     
     
       4. The inorganic acid salt of sibutramine as set forth in  claim 1 , wherein the sibutramine hydrogen sulfate is a third crystalline sibutramine hydrogen sulfate having an X-ray diffraction pattern in which peaks appear at 2θ values of 6.64, 10.24, 13.03, 15.04, 17.00, 17.53, 17.08, 19.06, 20.52, 22.72, 23.23, 24.23, 25.70, 26.40, and 27.57. 
     
     
       5. The inorganic acid salt of sibutramine as set forth in  claim 1 , wherein the sibutramine bromate is crystalline sibutramine bromate having an X-ray diffraction pattern in which peaks appear at 2θ values of 6.96, 11.48, 13.88, 16.64, 17.14, 18.14, 19.68, 20.92, 21.32, 21.86, 22.16, 22.86, 24.30, 26.16, 26.40, 27.42, 28.06, 28.32, 29.52, 31.58, 32.94, 34.54, 37.42, and 37.82. 
     
     
       6. The inorganic acid salt of sibutramine as set forth in  claim 1 , wherein the sibutramine phosphate monohydrate is crystalline sibutramine phosphate monohydrate having an X-ray diffraction pattern in which peaks appear at 2θ values of 7.66, 10.68, 11.06, 11.50, 14.46, 15.40, 15.74, 17.22, 17.84, 18.08, 18.98, 19.68, 21.18, 21.50, 21.88, 22.84, 23.18, 23.62, 24.42, 24.72, 25.98, 27.52, 28.38, 28.64, and 29.28. 
     
     
       7. A method of preparing sibutramine bromate comprising reacting sibutramine and bromic acid. 
     
     
       8. A method of preparing sibutramine phosphate or phosphate monohydrate comprising reacting sibutramine and phosphoric acid. 
     
     
       9. The method as set forth in  claim 7  or  8 , wherein the reaction takes place in an organic solvent selected from the group consisting of acetone, ethyl acetate, methanol, ethanol, isopropanol, acetonitrile, isopropyl ether, methylethyl ketone, dichioromethane and combinations thereof. 
     
     
       10. A pharmaceutical composition comprising an inorganic acid salt of sibutramine represented by the following Chemical Formula 1: 
       
         
           
           
               
               
           
         
         and a pharmaceutically acceptable diluent or carrier. 
       
     
     
       11. The pharmaceutical composition as set forth in  claim 10 , wherein the sibutramine hydrogen sulfate, sibutramine bromate or sibutramine phosphate is contained in a therapeutically effective amount of 1 to 50 mg. 
     
     
       12. A method of treating obesity, depression, Parkinson's disease, insulin-independent diabetes mellitus or epilepsy, comprising administering a—pharmaceutical composition comprising an inorganic acid salt of sibutramine represented by the following Chemical Formula 1: 
       
         
           
           
               
               
           
         
         and a pharmaceutically acceptable diluent or carrier. 
       
     
     
       13. The pharmaceutical composition as set forth in  claim 10 , wherein the composition is for treating obesity, depression, Parkinson's disease, insulin-independent diabetes mellitus, or epilepsy.